The overall goals of the proposed research are to elucidate the biochemical determinants of antiviral drug action and to develop synergistic drug combinations for the treatment of viral infections. In particular, I propose to study to the biochemical mechanisms by which the combination of 5'-amino-5'-deoxythymidine (5'-AdThd) and either iododeoxyuridine (IdUrd) or trifluorothymidine (CF3dUrd) produces therapeutic syngerism in the treatment of herpes simplex virus (HSV) infections. Two important components are involved in these interactions: a reduction in host cell toxicity and an increase in the antiherpes effect. We will analyze the mechanisms mediating both of these effects. Although 5'-AdThd is capable of reducing the host cell toxicity produced by either CF3dUrd or IdUrd, therapeutically important differences in the patterns of protection are evident. In order to effectively select combinations for in vivo evaluation and to design new combinations it is very important to understand the basis of this differential protection. Several alternative hypotheses are proposed which might explain the differences between CF3dUrd and IdUrd and the mechanisms by which therapeutic synergism is achieved when these agents are used in combination with 5'-AdThd. These hypotheses will be tested by analyzing drug action at two levels. Firstly, the patterns of drug uptake and metabolism will be determined in both uninfected intact cells and in cells which have been infected with various strains of HSV types -1 and -2. Then, based on the information obtained, the key sites of interaction will be pursued at the enzymological level. The efficacy of these and other drug combinations will be evaluated against a variety of HSV strains for two reasons. One goal is to identify an effective treatment for herpes genitalis and herpes encephalitis, two diseases which are generally refractory to drug therapy. The second is to elucidate the biochemical parameters which determine the effectiveness of drug treatment in herpes infections.